text: The sodium-calcium exchanger, also known as the Na/Ca exchanger or NCX, is an antiporter responsible for removing calcium from cells. This title encompasses a class of ion transporters that are commonly found in the heart, kidney, and brain. They use the energy stored in the electrochemical gradient of sodium to exchange the flow of three sodium ions into the cell for the export of one calcium ion. Though this exchanger is most common in the membranes of the mitochondria and the endoplasmic reticulum of excitable cells, it can be found in many different cell types in various species.
  Although the sodium-calcium exchanger has a low affinity for calcium ions, it can transport a high amount of the ion in a short period of time. Because of these properties, it is useful in situations where there is an urgent need to export high amounts of calcium, such as after an action potential has occurred. Its characteristics also enable NCX to work with other proteins that have a greater affinity for calcium ions without interfering with their functions. NCX works with these proteins to carry out functions such as cardiac muscle relaxation, excitation-contraction coupling, and photoreceptor activity. They also maintain the concentration of calcium ions in the sarcoplasmic reticulum of cardiac cells, endoplasmic reticulum of excitable and nonexcitable cells, and the mitochondria.
  Another key characteristic of this antiporter is its reversibility. This means that if the cell is depolarized enough, the extracellular sodium level is low enough, or the intracellular level of sodium is high enough, NCX will operate in the reverse direction and begin bringing calcium into the cell. For example, when NCX functions during excitotoxicity, this characteristic allows it to have a protective effect because the accompanying increase in intracellular calcium levels enables the exchanger to work in its normal direction regardless of the sodium concentration. Another example is the depolarization of cardiac muscle cells, which is accompanied by a large increase in the intracellular sodium concentration that causes NCX to work in reverse. Because the concentration of calcium is carefully regulated during the cardiac action potential, this is only a temporary effect as calcium is pumped out of the cell.
  The sodium-calcium exchanger's role in maintaining calcium homeostasis in cardiac muscle cells allows it to help relax the heart muscle as it exports calcium during diastole. Therefore, its dysfunction can result in abnormal calcium movement and the development of various cardiac diseases. Abnormally high intracellular calcium levels can hinder diastole and cause abnormal systole and arrythmias. Arrythmias can occur when calcium is not properly exported by NCX, causing delayed afterdepolarizations and triggering abnormal activity that can possibly lead to atrial fibrillation and ventricular tachycardia.
  If the heart experiences ischemia, the inadequate oxygen supply can disrupt ion homeostasis. When the body tries to stabilize this by returning blood to the area, ischemia-reperfusion injury, a type of oxidative stress, occurs. If NCX is dysfunctional, it can exacerbate the increase of calcium that accompanies reperfusion, causing cell death and tissue damage. Similarly, NCX dysfunction has found to be involved in ischemic strokes. Its activity is upregulated, causing a increased cytosolic calcium level, which can lead to neuronal cell death.
  The Na/Ca exchanger has also been implicated in neurological disorders such as Alzheimers disease and Parkinsons disease. Its dysfunction can result in oxidative stress and neuronal cell death, contributing to the cognitive decline that characterizes Alzheimers disease. The dysregulation of calcium homeostasis has been found to be a key part of neuron death and Alzheimers pathogenesis. For example, neurons that have neurofibrillary tangles contain high levels of calcium and show hyperactivation of calcium-dependent proteins. The abnormal calcium handling of atypical NCX function can also cause the mitochondrial dysfunction, oxidative stress, and neuronal cell death that characterize Parkinsons. In this case, if dopaminergic neurons of the substantia nigra are affected, it can contribute to the onset and development of Parkinsons disease. Although the mechanism is not entirely understood, disease models have shown a link between NCX and Parkinson's and that NCX inhibitors can prevent death of dopaminergic neurons.